Circadian misalignment has deleterious effects on metabolism, and contributes to the obesity and diabetes epidemics in the US. Recent discoveries implicate the nuclear receptor Rev-erb1 as a transcriptional link between the circadian clock and metabolism. The present proposal combines tissue-specific, genome-wide analysis of TF binding and epigenomic modifications, novel mouse genetic models, and sophisticated metabolic phenotyping to understand the physiological role of Rev-erb1 and Rev-erb2 in the coordination of circadian rhythms and metabolism. Specific Aim 1 is to determine the role of Rev-erb1 in the regulation of hepatic circadian rhythm and metabolism. The liver is a critical metabolic organ, and our preliminary data demonstrate fatty liver in mice lacking Rev-erb1. Genome-wide analysis of Rev-erb1 binding sites identifies lipid metabolic genes to which HDAC3 is recruited in a circadian manner. We hypothesize that this is a critical mechanism of circadian epigenomic control of hepatic lipid metabolism, and will test this by a combination of genome-wide approaches in informative and carefully phenotyped mouse genetic models. Specific Aim 2 is to determine the role of Rev-erb1 in adipose circadian rhythm and metabolism. Preliminary data show that mice lacking Rev-erb1 have increased white adipose tissue, and genome-wide analysis reveals binding of Rev-erb1 to a distinct set of metabolic genes. We will test the hypothesis that Rev-erb1 epigenomically controls fat- specific functions together with cooperating transcription factors. Specific Aim 3 is to determine the role of Rev- erb1 stabilization in circadian rhythm and metabolism, utilizing a novel mouse model in which Rev-erb1 is insensitive to the lithium-stimulated degradation pathway. Specific Aim 4 is to determine the role of Rev-erb2 in the regulation of circadian rhythm and metabolism. Knockdown and knockout models will test the hypothesis that Rev-erb2 has circadian and metabolic functions that are both unique and partly redundant with Rev-erb1. These integrative studies have important implications for understanding the links between circadian rhythm and metabolism that underlie the mechanism by which circadian misalignment exacerbates metabolic dysfunction, obesity, and diabetes. PUBLIC HEALTH RELEVANCE: In humans, circadian regulation is intimately linked to metabolic homeostasis, and circadian misalignment is now recognized as a risk factor for metabolic disorders including diabetes, obesity, and cardiovascular diseases that are of great significance due to their marked rise in modern societies, especially the United States. The nuclear receptor Rev-erb1 links circadian and metabolic physiology. Thus, understanding its integrative function will inform new approaches to metabolic diseases.